Norman, Aaron D.

Abstract Purpose: Volumetric breast density and body mass index (BMI) are increasingly used for breast cancer risk stratification. We examine if the effect of volumetric breast density on breast cancer risk increases with increasing BMI. Methods: Participants were from two case-control studies within mammography practices, the San Francisco Mammography Registry and the Mayo Clinic Rochester, Breast Screening Practice. Breast cancers were included if diagnosed between January 2007 and 2015 and with a screening full-field digital mammogram at least 6 months prior to diagnosis; the earliest mammogram within 5 years of diagnosis was selected. Up to three controls were matched to each case on age, race, date, mammography machine, and state of residence. Volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV) were measured using VolparaTM software. Breast cancer risk was assessed using logistic regression stratified by menopause status and adjusted for matching factors, family history of breast cancer, parity/age at first birth, and postmenopausal hormone therapy. Models for DV were additionally adjusted for NDV, and NDV models for DV. Multiplicative interactions were fit between BMI categories [<25 (underweight), 25-30 (normal weight) and >30 (overweight/obese) kg/m2] and VPD, DV, and NDV, and trend tests assessed for increasing odds ratios (OR) with increasing BMI. Results: A total of 781 premenopausal and 1850 postmenopausal breast cancers and 3535 controls were included in the analysis. Median age of premenopausal women was 45 years (IQR: 6.1) and 63.3 years (IQR: 14) for postmenopausal women. Cases vs. controls had greater VPD and DV for both premenopausal (VPD: 14.9% vs. 12.0%, DV: 74.1 cm3 vs. 64.4 cm3) and postmenopausal women (VPD: 6.8% vs. 6.1%, DV: 53.4 cm3 vs. 48.0 cm3)(all p's<0.001). Trends between increasing BMI and VPD were evident for both pre (ptrend=0.0007) and postmenopausal (ptrend=0.0005) women. Among premenopausal women, the odds ratio (OR) for breast cancer associated with a 10% increase in VPD was of 1.39, 2.19 and 2.88 for BMI <25, 25-30 and >30 kg/m2 (p-trend=0.0007), respectively. For DV, OR's were 1.39, 1.33 and 1.51 for a 1 SD increase in DV, respectively, though the interaction with DV was not significant (ptrend=0.68). Among postmenopausal women, a 10% increase in VPD was associated with OR's of 1.35, 2.03, 3.6 for BMI <25, 25-29, >30-kg/m2 (ptrend =0.0001), respectively, and 1.31, 1.34 and 1.65 for a 1 SD increase in DV (ptrend =0.01), respectively. Associations between NDV and breast cancer risk did not differ by BMI category for premenopausal (ptrend =0.52) or postmenopausal (ptrend =0.07) women. Conclusions: The effect of VPD on breast cancer risk is strongest in overweight/obese women. As volumetric breast density and BMI are commonly used in clinical risk stratification, these differences in risk have high clinical relevance for informing prevention decisions. Citation Format: Natalie J. Engmann, Christopher G. Scott, Matthew R. Jensen, Stacey J. Winham, Lin Ma, Kathleen R. Brandt, Amir Mahmoudzadeh, Serghei Malkov, Dana Whaley, Carrie Hruska, Fang Fang Wu, Diana L. Miglioretti, Aaron D. Norman, John Heine, John Shepherd, Vernon S. Pankratz, Celine M. Vachon, Karla Kerlikowske. Overweight and obese women with high volumetric breast density at high breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3226.

Abstract CLL is a highly heritable cancer with first degree relatives of CLL cases having a 7.5-fold increased CLL risk. Genome-wide association studies (GWAS) and linkage studies have been performed to study inherited predisposition; however a larger proportion of heritability to CLL remains unexplained. Rare coding variants might account for the missing heritability information. Inherited loss of function variants in shelterin complex genes (POT1, ACD, TERF1, TINF2, TERF2, TERF2IP- involved in telomere regulation), CDK1 (critical for cell division) and ATM (tumor suppressor gene) have been found to co-segregate in CLL families and be enriched in CLL cases using exome-wide sequencing data. Our study evaluates rare germline variants from these suspect genes segregating in CLL families who are followed at the Mayo Clinic. Using whole exome sequencing (WES), we sequenced 93 CLL families with at least 2 reported CLL cases consisting of 443 individuals: 160 with CLL, 73 with monoclonal B-cell lymphocytosis (MBL), and 210 relatives. DNA was extracted from buccal cells, coding exons were selectively captured using Agilent 50Mb and SureSelect Human All Exon V4 capture kits; sequencing was performed using Illumina HiSeq 2000. Mayo Clinic's DNASeq pipeline uses Novoalign (initial read alignment), Picard (marking duplicate reads), and the Genome Analysis Toolkit (GATK) for local realignment, recalibration, and variant calling. The variant discovery step leverages GATK's HaplotypeCaller in per sample mode and all of the samples across the cohort are jointly genotyped together. All called variants are evaluated with GATK's Variant Quality Score Recalibration tool and annotated for biological relevance (BIOR). Quality control included removing variants that had <75% call rate across the two capture kits, <8x coverage, or phred score<10, resulting in 317,666 remaining variants. Of these, over 80% of the coding sequence had a median read depth of 23 reads. In our pedigrees, we searched for rare variants within the genes described above. We identified suspect variants with the following criteria: 1) enriched in CLL and MBL samples compared to unaffected samples; 2) multiple affected members with the variant within a family; 3) variants present in all sequenced affecteds within the family; 4) rarely seen in an in-house database of non-cancer controls or 1K Genomes; and 5) predicted to have a functional damaging effect (using SIFT). We identified three novel rare missense variants, defined as functionally deleterious, which each co-segregated within a CLL family. Specifically, these variants from shelterin complex genes; POT1 (rs116916706), TERF2IP (rs138458227), and TERF2 (rs749171225), met the criteria. This study further highlights telomere dysregulation as a key process in CLL development. Investigating rare variants within CLL pedigrees with WES can help identify germline variants impacting predisposition to familial CLL. Citation Format: Alyssa I. Clay-Gilmour, Daniel R. O'Brien, Sara J. Achenbach, Celine M. Vachon, Kari G. Chaffee, Timothy G. Call, Jose F. Leis, Aaron D. Norman, Brian F. Kabat, Sameer A. Parikh, Neil E. Kay, Esteban Braggio, James R. Cerhan, Susan L. Slager. Rare germline variants segregating in chronic lymphocytic leukemia (CLL) families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1226.

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

Abstract Background: Reductions in breast density with tamoxifen and aromatase inhibitors may be an intermediate marker of treatment response. We compare changes in volumetric breast density among breast cancer cases using tamoxifen or aromatase inhibitors (AI) to untreated women without breast cancer. Methods: Breast cancer cases with a digital mammogram prior to diagnosis and after initiation of tamoxifen (n = 366) or AI (n = 403) and a sample of controls (n = 2170) were identified from the Mayo Clinic Mammography Practice and San Francisco Mammography Registry. Volumetric percent density (VPD) and dense breast volume (DV) were measured using Volpara (Matakina Technology) and Quantra (Hologic) software. Linear regression estimated the effect of treatment on annualized changes in density. Results: Premenopausal women using tamoxifen experienced annualized declines in VPD of 1.17% to 1.70% compared with 0.30% to 0.56% for controls and declines in DV of 7.43 to 15.13 cm3 compared with 0.28 to 0.63 cm3 in controls, for Volpara and Quantra, respectively. The greatest reductions were observed among women with ≥10% baseline density. Postmenopausal AI users had greater declines in VPD than controls (Volpara P = 0.02; Quantra P = 0.03), and reductions were greatest among women with ≥10% baseline density. Declines in VPD among postmenopausal women using tamoxifen were only statistically greater than controls when measured with Quantra. Conclusions: Automated software can detect volumetric breast density changes among women on tamoxifen and AI. Impact: If declines in volumetric density predict breast cancer outcomes, these measures may be used as interim prognostic indicators. Cancer Epidemiol Biomarkers Prev; 26(6); 930–7. ©2017 AACR.

Abstract Breast density represents the stromal and epithelial tissue in the breast and is a strong risk factor for breast cancer. Reductions in breast density attributable to tamoxifen (TAM) and aromatase inhibitors (AI) may be associated with reduced risk of first primary and subsequent breast cancer. Studies assessing breast density changes have principally used two-dimensional measures. We assess changes in breast density following initiation of TAM and AI using two automated volumetric density measures that have shown strong associations to breast cancer risk. Breast cancer cases with a full field digital mammogram (FFDM) prior to diagnosis (index mammogram) and after initiation of TAM (n = 379) or AI (n = 425) were identified from the Mayo Clinic Mammography Practice and the San Francisco Mammography Registry. Volumetric percent density (VPD) and dense volume (DV) were measured on 4-view FFDM using VolparaTM (Matakina Technology) and QuantraTM (Hologic) automated software. We used linear regression to assess the effect of treatment on mean annualized change in VPD and DV (change from index to last mammogram divided by time interval) for each software type, adjusting for age, body mass index (BMI) and density at index mammogram. The median time between index mammogram and cancer diagnosis was 0.6 months (IQR: 0.2, 2.2) and median time between index and last mammogram was 3 years (IQR: 2.0, 3.9). Women on TAM were younger, had lower BMI and higher baseline VPD and DV relative to women on AI (Table). An annual decrease in VPD and DV was observed with both TAM and AI. Both Volpara and Quantra estimated a similar magnitude of change in VPD in women on TAM and AI, and a greater change in DV with TAM. Our findings suggest that both Volpara and Quantra can assess volumetric changes in breast density among women on hormone therapy. If declines in volumetric density correlate with a reduction in breast cancer risk, these automated measures could be used in clinical practice to assess response to therapy. Annualized changes in volumetric breast density estimated by linear regression.Tamoxifen (n = 379)Aromatase Inhibitors (n = 425)Baseline Median (IQR)Annualized Change (95% CI)*Baseline Median (IQR)Annualized Change (95% CI)*Age at Diagnosis50.0 (45.0, 60.0)–63.0 (58.0, 71.0)–Body Mass Index (BMI)23.6 (21.5, 26.8)–25.7 (22.7, 29.9)–Time Interval¥3.0 (2.1, 3.9)–3.0 (2.1, 3.9)–VolparaPercent Density (VPD,%)11.6 (6.8, 18.8)-0.17 (-0.27, -0.10)7.2 (5.0, 11.0)-0.19 (-0.29, -0.12)Dense Volume (DV, cm3)64.7 (45.4, 90.9)-0.90 (-1.45, -0.48)51.9 (38.9, 69.9)-0.52 (-0.93, -0.23)QuantraPercent Density (VPD,%)14.5 (9.2, 20.2)-0.42 (-0.59, -0.28)9.9 (7.1, 14.5)-0.38 (-0.54, -0.25)Dense Volume (DV, cm3)94.0 (58.0, 144.0)-2.20 (-3.52, -1.19)80.0 (49.0, 128.0)-0.95 (-1.85, -0.35)IQR = Interquartile range ¥ Median number of years between index mammogram and last mammogram post-initiation of therapy. *Annualized change estimated as change from index to last mammogram divided by time interval and adjusted for study site, age at diagnosis, BMI and density at index mammogram. Citation Format: Natalie J. Engmann, Celine M. Vachon, Christopher G. Scott, Matthew R. Jensen, Lin Ma, Kathleen R. Brandt, Amir P. Mahmoudzadeh, Serghei Malkov, Dana H. Whaley, Carrie B. Hruska, Fang F. Wu, Stacey J. Winham, Diana L. Miglioretti, Aaron D. Norman, John J. Heine, John Shepherd, V Shane Pankratz, Karla Kerlikowske. Longitudinal changes in volumetric breast density with adjuvant endocrine therapy among women with breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3424.

Abstract Percent mammographic density (PMD) is a risk factor for estrogen receptor (ER)-positive and ER-negative invasive breast cancer (BC). Gene expression profiling has identified molecular signatures that classify invasive BC into distinct subtypes that vary in their clinical behavior, response to treatment and likely, etiology. Immunohistochemical (IHC) staining of tumor sections using antibody panels can be used to classify these ‘intrinsic’ molecular subtypes. We evaluated whether density measures [PMD, absolute dense area (DA) and non-dense area (NDA)], are associated equally with all ‘intrinsic’ molecular subtypes. Pooled analysis of six cohort or case-control studies included 3492 women with invasive BC and 10,148 without, who underwent screening mammography a median 4 years prior to diagnosis (for cases). PMD, DA, and NDA were assessed from digitized film-screen mammograms using a computer-assisted thresholding technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+ (PMD) or into quartiles (DA and NDA). Receptor status was abstracted from pathology records and supplemented by IHC staining. We classified tumors as Luminal A (ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (TN) (ER-/PR-/HER2-). For TN, we also differentiated basal-like tumors (positive for EGFR and/or CK 5/6) from unclassified (negative on both markers). We used polytomous logistic regression to calculate the odds ratio (OR) of each ‘intrinsic’ subtype of BC by categories of PMD, DA or NDA, adjusting for age, body mass index and study. We tested for statistical heterogeneity of associations by subtype. Of 3492 invasive BC cases, 2217 (63%) were classified as Luminal A, 747 (21%) as Luminal B, 159 (5%) as HER2 expressing, and 369 (11%) as TN. Of TN, 203 were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) unclassified. PMD was associated with BC risk across all subtypes. For Luminal A, compared to women with 11-25% PMD (reference), women with 0-10% had a reduced risk of BC (OR = 0.63 [95% confidence interval: 0.55, 0.74]) while women with 26-50% had an OR = 1.5 [1.3, 1.7] and women with 51%+ had the highest risk, OR = 2.3 [2.0, 2.7]. Similar BC associations were seen across PMD categories when comparing the five subtypes (P-heterogeneity = 0.63). Similar trends were seen for DA and BC across the five subtypes (P-het = 0.25). NDA was inversely associated with BC across subtypes, and there was suggestion of a stronger inverse trend among HER2-expressing BC compared to other subtypes (P-het = 0.09). Our results suggest mammographic density measures are associated with all ‘intrinsic’ molecular subtypes. However, NDA may be more strongly inversely associated with HER2-expressing than other subtypes. Understanding the importance of density measures for BC subtypes has significance for subtype-specific risk models. Citation Format: Aaron D. Norman, Rulla M. Tamimi, Christopher G. Scott, Kimberly A. Bertrand, Matthew R. Jensen, Daniel W. Visscher, Fergus J. Couch, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew Beck, Vernon S. Pankratz, Karla Kerlikowske, Celine M. Vachon. Association of mammographic density measures and breast cancer ‘intrinsic’ molecular subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2593.

Abstract Gene expression profiling has identified molecular subtypes that classify invasive breast cancers into distinct categories that vary in their clinical behavior and response to treatment. These subtypes highlight the many possible biologically and clinically distinct types of breast cancer. Immunohistochemical (IHC) staining of tumor sections using antibody panels has been used as a surrogate for the molecular subtypes identified through gene expression profiling, resulting in a set of intrinsic molecular subtypes. Given the heterogeneity within breast cancer, one might expect that different risk factors influence specific subtypes of breast cancer through various etiologic pathways. We evaluated whether percent mammographic density (MD), the proportion of fibroglandular or white tissue on a mammogram and one of the strongest and most consistent risk factors for breast cancer, is associated equally with all intrinsic molecular subtypes. Data were pooled from six cohort or case-control studies including 3389 women with invasive breast cancer and 9860 without, who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms (for cases, at a median 4 years prior to diagnosis) using a computer-assisted threshold technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+. Receptor status was abstracted from clinical pathology records and supplemented by IHC staining of tumor sections or microarrays. With estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) information, we classified tumors into the intrinsic molecular subtypes: Luminal A ( ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (ER-/PR-/HER2-). For cancers found to be triple negative (TN), we also stained for epidermal growth factor receptor (EGFR) and cytokeratins (CK) 5/6 to differentiate basal-like tumors (positive for EGFR and/or CK 5/6) from the unclassifieds (negative on both EGFR and CK 5/6). We used polytomous logistic regression to calculate the odds (OR) of each of the intrinsic subtypes of breast cancer by categories of percent MD, adjusting for age, BMI and study. Contrasts were constructed and tested within the polytomous model framework to investigate differences in the strength of association of percent MD across subtypes. On average, cases were slightly older (56.4 years [SD=11.3]) than controls (55.8 [10.9]). Of the 3389 invasive breast cancer cases, 2146 (63%) were classified as Luminal A, 709 (21%) as Luminal B, 169 (5%) as HER-2 expressing, and 365(11%) as triple negative (TN). Of the TN tumors, 203 had tumor tissue available and were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) as unclassified. Percent (%) MD was associated with breast cancer risk across all intrinsic subtypes. For Luminal A, compared to women with 11-25% MD (reference), women with 0-10% MD had a reduced risk of breast cancer (OR=0.64 [95% confidence interval (CI): 0.55, 0.74]) while women with 26-50% MD had an OR=1.5 (1.3,1.7) and women with 51%+ MD had the highest risk, OR=2.4 (2.0, 2.8). Similar associations were seen for Luminal B, HER2 expressing, and TN across percent MD categories. The small differences among the percent MD-breast cancer associations observed for the different subtypes were not statistically significant, either when comparing the four (Luminal A, Luminal B, HER-2 expressing and TN; p=0.61) or five categories of subtypes (Luminal A, Luminal B, HER-2 expressing, basal-like, unclassified; p=0.66). Our results suggest percent MD is a risk factor for all intrinsic molecular subtypes. Additional study is needed to examine whether these results hold for younger and older aged women. Understanding the importance of mammographic density measures for subtypes of breast cancer has significance for development of subtype-specific risk models. Citation Format: Celine Vachon, Rulla Tamimi, Yunn-Yi Chen, Christopher Scott, Kimberly Bertrand, Matthew Jensen, Daniel Visscher, Aaron Norman, Fergus Couch, John Shepherd, Bo Fan, Fang-Fang Wu, Lin Ma, Andrew Beck, Steve Cummings, V. Shane Pankratz, Karla Kerlikowske. Mammographic density: A risk factor for all breast cancers or only specific subtypes? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA22.

Abstract Introduction: We recently reported the percentage of mammographic density (MD) to be a breast cancer risk factor across tumor characteristics and age groups. Yet, we noted stronger associations for tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women. We extend this initial study to investigate whether these associations with aggressive disease are due to the underlying associations of absolute dense or non-dense area, or both, with breast cancer risk. Methods: Data were pooled from six studies including 3517 women with invasive breast cancer and 8558 without. Dense area and non-dense area were assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We standardized dense and non-dense area measurements made within each study and categorized into quartiles based on the control distribution for pooled analyses. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (ER, PR) status by age (<55, 55-64, and ≥65 years), adjusting for continuous age, body mass index, and study site. Results: Absolute dense area was associated with increased breast cancer risk [odds ratios (ORs) Q1 vs Q2: 0.67, Q3 vs Q2: 1.25, Q4 vs Q2: 1.62] and non-dense area was associated with decreased breast cancer risk (ORs: Q1 vs Q2: 1.44, Q3 vs Q2: 0.89, Q4 vs Q2: 0.71) overall and across all age groups. Positive associations for absolute dense area were observed across all invasive tumor characteristics. Stronger associations were noted for larger tumors across all ages (p-trend <0.01). Among women <55 years, stronger associations were observed for ER+ vs ER- [p-heterogeneity (het) = 0.02] and PR+ vs PR- tumors (p-het = 0.02). Non-dense area was inversely associated with all tumor characteristics evaluated except for tumors <1.1 cm, for which no association was present. The inverse association was stronger for larger tumors, particularly for women <55 years (p-trend <0.01). Also among women <55 years, a stronger inverse association with non-dense area was observed for ER- vs. ER+ tumors (p-het = 0.02). Conclusion: These results suggest the strong association we previously observed of high percent MD and ER-negative disease in women <55 years could be explained by the low amount of non-dense area in these women. Further research is warranted to clarify the possible differential associations of absolute dense and non-dense area on breast cancer risk according to tumor characteristics. Citation Format: Kimberly A. Bertrand, Christopher G. Scott, Rulla M. Tamimi, Matthew R. Jensen, V. Shane Pankratz, Aaron Norman, John Shepherd, Yunn-Yi Chen, Karla Kerlikowske, Celine M. Vachon. Dense and non-dense mammographic area and risk of breast cancer by age and tumor characteristics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3279. doi:10.1158/1538-7445.AM2014-3279

Abstract Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages <55 years. To provide insight into these associations, we examined the components of PMD [dense area (DA) and nondense area (NDA)] with breast cancer subtypes. Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression. Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend <0.001] and NDA was associated with decreased risk [ORs for quartiles: 1.39, 1.00 (Ref), 0.88, 0.72; Ptrend <0.001] across all ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (Ptrend < 0.001) but no differences by nodal status. Among women <55 years, DA was more strongly associated with increased risk of ER+ versus ER− tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER− versus ER+ tumors (Phet = 0.03). Conclusions: DA and NDA have differential associations with ER+ versus ER− tumors that vary by age. Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.

Abstract Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the most common adult leukemia in the United States. Prior studies in Olmsted County, Minnesota, showed a CLL age and sex adjusted incidence rate of 6.6 per 100,000 during 1985-89. Subsequently, the definition of CLL is now based on the 2008 International Workshop on CLL (IWCLL) Guidelines. Individuals having a CLL immunophenotype by flow cytometry are classified as CLL if the absolute B-cell count (ABC) is >5 x 109/L or classified as monoclonal B-cell lymphocytosis (MBL) if ABC is <5 x 109/L. To assess the impact of these changes on the incidence of CLL and clinically discovered MBL, we conducted an incidence study in Olmsted County for the years 2000-2010. Methods Using diagnostic indexes available through the Rochester Epidemiology Project and the Mayo CLL database, we identified all CLL and clinically identified MBL cases from 2000-2010. Incidence rates and demographics were compared between the older National Cancer Institute-Working Groups 1996 guidelines (NCI-WG 96) defined as absolute lymphocyte count (ALC)> 5 x 109/L and the IWCLL 2008 guidelines defined as ABC > 5 x 109/L. Incidence rates were age and sex adjusted using the 2010 US white population. Time to treatment (TTT) survival analyses was from time of diagnosis to date of first treatment or last follow-up and Cox regression analysis was used. Results Using the NCI-WG 96 classification, there were 8 MBL cases and 115 CLLs in whom 61% were Rai stage 0, 34% were Rai stage 1-2, and 5% were Rai stage 3-4. Using the IWCLL 2008 classification, there were 44 MBL cases and 79 CLLs in whom 43% Rai stage 0, 49% were Rai stage 1-2 and 8% Rai stage 3-4. Median ALC at diagnosis was 8.1 x 109/L for CLL and 5.9 x 109/L for MBL. Median ABC count at diagnosis was 7.1 x 109/L for CLL and 2.8 x 109/L for MBL. The age and sex adjusted incidence rate (per 100,000) for CLL for 2000-2010 was 10.0 using NCI-WG 96 and 6.8 using IWCLL 2008. Rates for MBL were 0.66 using NCI-WG 96 and 3.5 using IWCLL 2008. The median TTT for CLL was 9.2 years using NCI-WG 96 and 6.5 years by IWCLL 2008. Discussion This study demonstrates that reclassification of CLL using the IWCLL 2008 guidelines decreases CLL incidence relative to the NCI-WG 96 criteria. For the first time, this population based study also establishes an incidence rate for clinically identified MBL. Approximately 50% of previously labeled Rai 0 CLL are now reclassified as MBL. Re-classification increases the percent of Rai stage 1-2 and decreases the percent of Rai 0 cases at diagnosis. Reclassification also substantially shortens the median TTT for newly diagnosed CLL cases classified by the 2008 criteria relative to the NCI-WG 96 criteria. In summary, the IWCLL 2008 reclassification has significant implications for incidence studies, staging, and prognosis of CLL and MBL. Citation Format: Aaron D. Norman, Timothy G. Call, Curtis A. Hanson, Neil E. Kay, Clive S. Zent, Wei Ding, James R. Cerhan, Sara J. Achenbach, Kari G. Rabe, Celine M. Vachon, Emily J. Hallberg, Tait D. Shanafelt, Susan L. Slager. Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Olmsted county, 2000-2010: impact of the 2008 International Workshop on CLL Guidelines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2287. doi:10.1158/1538-7445.AM2013-2287